The carbon-fluorine bond is commonly found in pharmaceutical and agrochemical products, because it is generally metabolically stable and the fluorine atom acts as a bioisostere of the hydrogen atom (Ann M. Thayer “Fabulous Fluorine” Chemical and Engineering News, June 5, 2006, Volume 84, pp. 15-24). Nowadays around 20% of all pharmaceutical compounds and 30-40% of agrochemicals on the market contain fluorine. Fluorination and fluoroalkylation are the two major synthetic methods to prepare selectively fluorinated organic compounds. The monofluoromethylation (selective introduction of a CH2F group into the organic molecule) is less studied than fluorination.
The exploration of di- and monofluoromethylated compounds as organic biologically active compounds has emerged recently. As a result, a variety of structurally diverse CH2F-containing drugs have been developed, such as: Afloqualone, Fluticasone Propionate (Jinbo Hu; Wei Zhang; Fei wang; Chem. Commum., 2009, 7465-7478), the anaesthetic Sevoflurane, Fluticasone Furoate.
The efficient and selective incorporation of monofluoromethylated moieties into the organic molecule is beneficial for the synthesis of the target molecule. The process is usually carried out directly using CH2FBr or indirectly, using CH2BrI or CH2ClI, among others. These compounds are known as hydrochlorofluorocarbons or freons (HCFCs), which is a subclass of chlorofluorocarbons (CFCs).
Every permutation of fluorine, chlorine, and hydrogen on the methane and ethane core has been examined and most have been commercialized. Furthermore, many examples containing bromine are known for higher numbers of carbon as well as related compounds. The use of this class of compounds includes refrigerants, blowing agents, propellants in medicinal applications, and degreasing solvents (M. Rossberg et al. “Chlorinated Hydrocarbons” in Ullmann's Encyclopedia of Industrial Chemistry 2006, Wiley-VCH, Weinheim).
Unfortunately, due to their high stability, CFCs do not decompose in the lower atmosphere as many industrial chemicals do. In fact they are accumulating and eventually rise to the stratosphere. Ultraviolet radiation in the stratosphere breaks the CFCs apart, and the released chlorine atoms destroy the ozone layer. For this reason, the manufacture of such compounds is being phased out according to the Montreal Protocol (Pool, R. 1989. The elusive replacements for CFCs. Science 242: 666). Under the Montreal Protocol, it was agreed to start reducing their consumption and production in 2015.
Recently, Prakash et al. reported a new electrophilic monofluoromethylation reagent for direct transfer of +CH2F (S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate) to certain nucleophiles such as sulfonic acids, tertiary amines, imidazole derivatives, and phosphine (G. K. Surya Prakash; Istvan Ledneczki; Sujith Chacko; George A. (Olah; Org. Lett., vol. 10, No.4, 2008).